1. Field of the Invention
This invention pertains to new adenosine receptor agonists and methods of their use. More particularly, this invention provides a genus of sulfonamido derivatives with a conserved ethyl uronamide group.
2. Background
Adenosine exerts a number of physiological functions through activation of four cell membrane receptors classified as A1, A2A, A2B and A3. The most recently discovered A3 subtype has been the subject of intensive pharmacological characterization. Although all adenosine subclasses belong to the G protein-coupled receptors they are associated with different second messenger systems. The A3 subtype is believed to have a characteristic second messenger profile, in that it has been shown to mediate adenylyl cyclase inhibition and phospholipase C activation.
It is also believed that the adenosine A3 receptor may play a basic role in modulation of cerebral ischemia, inflammation, hypotension, ischemic heart pre-conditioning and asthma. This has made the A3 receptor a therapeutic target on cell growth, on apoptosis, malignant cell growth, on leukemic Jurkat T cells, on human malignant melanoma A375 cell line and on human neutrophils. The human cloned A3 adenosine receptor was first characterized with N6-(4-amino-3-[125I]iodobenzyl)adenosine.
It is believed that the presence of an N6 benzyl moiety in the adenosine structure provides a significant increase in A3 receptor affinity and selectivity. It is also believed that a methyl or ethyl uronamide moiety confers better affinity and selectivity at the A3 adenosine receptor. This combination of substitutions is present in N6-(3-iodo-benzyl)-adenosine-5′-N-methyl-uronamide (IB-MECA). IB-MECA is 50 fold selective for the A3 receptor versus either the A1 or A2A receptors. A selective radioligand, the [125I]-N6-(4 amino-3-iodo-benzyl)-adenosine-5′-N-methyl-uronamide ([125I]-AB-MECA) has also been developed. This compound has a high affinity, although less selectivity, but is still considered to be a standard agonist for the A3 adenosine receptor.
It is also thought that substitutions at the 2-position on the benzyl group with halogen, methylamino or thiomethyl groups increase both affinity and selectivity at the A3 receptor subtype. Substituents at the 3-position on the benzyl group also appear to be well tolerated. Both affinity and selectivity for the A3 receptor subtype seems to be related more to the type of substitution on the phenyl ring than to the position of the substituent.
Purine and ribose-modified adenosine analogs have been studied for their affinity at rat A3 adenosine receptors, but these compounds have typically not shown a better profile with respect to reference compounds. Several modifications utilized have suggested that: i) deaza derivatives are well tolerated at the A3 receptor; ii) substitutions at the 8 position are detrimental in terms of affinity; iii) carbocyclic nucleosides exhibit, in general, weak affinity at all receptor subtypes; iv) replacement of 6-NHCH2 linkage with hydroxylamino or hydrazino moieties is well tolerated; v) substitution of 4′ hydrogen with a methyl group retains agonist activity and selectivity at rat A3 adenosine receptors.